P771: PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA AND CLINICALLY SIGNIFICANT EXTRAVASCULAR HEMOLYSIS ON RAVULIZUMAB/ECULIZUMAB SHOWED HEMOGLOBIN RESPONSE SUPERIORITY WITH ADD-ON DANICOPAN VS PLACEBO
Authors: Jong Wook Lee, Morag Griffin, Jin Seok Kim, Lily L L Wong, Caroline Piatek, Deepak Jain, Peng Liu, Gleb Filippov, Flore Sicre de Fontbrune, Antonio Maria Risitano, Austin Kulasekararaj
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Approximately 10–20% of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab [Rav]; eculizumab [Ecu]) experience signs and symptoms of clinically significant extravascular hemolysis (cs-EVH). First-in-class oral factor D inhibitor danicopan (ALXN2040) is being investigated as add-on treatment to Rav/Ecu for pts with PNH and cs-EVH. Aims: ALPHA (NCT04469465) is an ongoing, phase 3, randomized, double-blind, placebo-controlled clinical trial designed as a superiority study to assess efficacy and safety of danicopan vs placebo add-on therapy in pts with PNH and cs-EVH on Rav/Ecu. Efficacy and safety data from the 12-wk primary treatment period (TP1) are presented. Methods: Adult pts with PNH and cs-EVH (hemoglobin [Hgb] ≤9.5 g/dL; absolute reticulocyte count [ARC] ≥120x109/L) on ≥6 mo of Rav/Ecu were randomized 2:1 to receive danicopan or placebo add-on therapy for 12 wks (TP1). At wk 12, placebo arm pts switched to danicopan and danicopan arm pts continued danicopan for another 12 wks. Initial danicopan dose of 150 mg thrice daily (TID) can be escalated to 200 mg TID based on clinical response at investigator discretion. Primary endpoint: change from baseline to wk 12 in Hgb. Secondary endpoints: proportion of pts with Hgb increase ≥2 g/dL at wk 12 in absence of transfusion, proportion of pts with transfusion avoidance through wk 12, and change from baseline to wk 12 in Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-Fatigue) score and ARC. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory abnormalities. Results: As of June 28, 2022, 73 pts were randomized; 63 pts were included in this planned interim efficacy analysis set (danicopan n=42; placebo n=21). Baseline characteristics were similar between arms (Table). All patients were transfusion dependent within 6 mo at baseline. The primary endpoint was met with danicopan plus Rav/Ecu, resulting in a clinically meaningful and statistically significant increase in Hgb from baseline to wk 12 vs placebo plus Rav/Ecu (least squares mean change from baseline [SE] 2.94 [0.211] g/dL vs 0.50 [0.313] g/dL; P<0.0001; Table). All 4 key secondary endpoints met statistical superiority in favor of danicopan plus Rav/Ecu vs placebo plus Rav/Ecu (Table). Effective control of lactate dehydrogenase was maintained with danicopan or placebo plus Rav/Ecu. The safety analysis set comprised 49 and 24 pts in the danicopan and placebo arms, respectively. Mean (SD) study drug compliance was 98.8% (3.74); 11/49 (22.4%) pts were escalated to 200 mg TID. Overall, 71.4% (n=35 pts; 106 events) and 62.5% (n=15 pts; 65 events) of pts had ≥1 TEAE in the danicopan and placebo arms, respectively; no TEAEs were grade 4 or 5 in severity. TEAEs of liver enzyme elevations were reported in 12.2% of pts in the danicopan arm and 8.3% of pts in the placebo arm; none were considered serious. One pt in each arm discontinued treatment due to liver enzyme elevations. Serious AEs were reported by 2 pts in each arm (danicopan: cholecystitis, COVID-19; placebo: anemia, abdominal pain); none were considered related to study drug. There were no deaths, meningococcal infections, or discontinuations due to hemolysis. Summary/Conclusion: These are the first results from a phase 3 placebo-controlled trial of the oral factor D inhibitor danicopan as add-on therapy to Rav/Ecu in pts with PNH and cs-EVH. Danicopan as add-on to Rav/Ecu significantly improves Hgb and reduces need for transfusion by addressing cs-EVH while maintaining control of IVH with a favorable benefit risk profile.Keywords: Paroxysmal nocturnal hemoglobinuria (PNH), Phase III